The goals of the pediatric HIV research effort are to conduct translational research aimed at developing improved and novel therapies for children with HIV infection and HIV-associated malignancies, to understand the pathogenesis of pediatric HIV disease, and study impact of pediatric HIV disease on the patients and their families. Both antiretroviral and immunologic approaches for HIV therapy are currently being investigated. This work is currently being performed by Drs. Steven Zeichner, Lauren Wood, Rohan Hazra, Carol Worrell, and other members of the Pediatric Working Group in HAMB. A major protocol investigating the use of tenofovir, a new nucleotide analog reverse transcriptase inhibitor in pediatric patients who have failed therapy with several other antiretroviral agents continued and began to yield published results. The study aims to obtain the pharmacokinetic and safety data needed to use the drug in the pediatric population. The study also aims to investigate several important aspects of pediatric HIV pathogenesis, such as the ability of highly experienced pediatric patients infected with resistant virus to respond new rounds of therapy and the potential for immune reconstitution in those patients, the development and evolution of antiviral resistance in pediatric patients, strategies for optimizing pediatric HIV therapy, particularly for highly experienced patients, and toxicities that may be associated with the therapy. We have described the tenofovir pharmacokinetic data obtained in the study in a paper that is in press. We are now engaged in analyzing the longer term safety data and the clinical, immunological, and virologic response data. Overall, the responses were better than anticipated in the highly antiretroviral experienced population enrolled in the study, but some patients appeared to experience potentially concerning decreases in bone mineral density. We have begun enrollment in another new protocol aimed at studying a novel therapeutic drug monitoring approach to antiretroviral therapy in children. In this study, we obtain initial viral resistance genotypes and inferred viral resistance phenotypes using the genotypes, design an optimal antiretroviral regimen based on that data and the patient's history, and establish a target plasma level for the protease inhibitor component of the antiretroviral regimen. After initiation of therapy, we measure plasma drug levels, compare them to the target levels, and increase the dose of the drug if the levels do not exceed the target levels. The protocol also includes extensive studies of adherence to antiretroviral therapy. If the strategy proves practical and effective, it may lead to improved approaches to therapy with greater responses. We continue to study the long-term virological and immunological effects of highly active antiretroviral therapy including a protease inhibitor and, in particular, the ability of such a regimen to effect immune reconstitution. The protease inhibitors have been used in children at the NCI longer than anywhere else and this ongoing experience may prove important for assessing the very long term response to highly active antiretroviral therapy in children. Results suggest that some patients on long-term therapy have immunologic improvement without sustained drops in their viral load. We have also examined some of the clinically problematic toxicities that may accompany long term antiretroviral therapy, describing the risks for lipodystrophy and dyslipidemia of long term protease inhibitor therapy, identifying an association between the onset of puberty and lipodystophy, and better viral load responses and dyslipidemia. Analysis of completed a trial investigating the effects of IL-2 and a trial of a gp120-depleted whole virus HIV therapeutic vaccine showed improvements in both quantitative and qualitative measures of immune function. Evaluation of thymic imaging in patients receiving immune-based therapies demonstrated that although administration was associated with quantitative improvements in absolute and nave CD4 counts as well as improvements in immune function, these improvements did not correlate with changes in thymus volume. In a study of ddI (didanosine) and hydroxyurea, stavudine, and efavirenz as a protease-sparing salvage regimen, decreases in markers of immune activation and increases in CD4 cell counts occurred despite virologic rebound. Intensive studies characterizing viral resistance demonstrated that genotypic and phenotypic resistance to ddI and d4T was intermittent and did not correlate with virologic rebound, but was associated with a sustained decrease in viral replication capacity, suggesting a possible independent treatment effect on immune dysregulation. To further explore the potential impact of alterations in replication capacity and viral fitness, a pilot study investigating the use of 5-fluorouracil (5FU) in combination with antiretroviral agents as a salvage regimen for heavily treatement-experienced patients is planned. We have also written a protocol, in collaboration with the Vaccine Research Center, NIAID, to test a DNA-adenovector prime-boost therapeutic vaccine in HIV-infected children with well-controlled disease. This study is aimed at assessing the safety of the vaccines, with some efficacy measures as an approach to developing an approach to enhancing the anti-HIV immune response in children who may have an excellent likelihood of maintaining and reconstituting immune function, and who may be at increased risk of decreasing adherence to therapy as they enter adolescence. Several additional protocols that investigate new antiretroviral agents in children are under development, and several of these studies will be conducted together with industrial collaborators. The pediatric HIV research effort has a significant component aimed at understanding the neuropsychological dimensions of pediatric HIV disease. Recent results from neuropsychological studies included the finding that some patients with good viral load responses may still experience neurocognitive declines, presumably due to HIV effects on the CNS and a study that examined how family coping strategies are associated with the medical and behavioral functioning of the child and family. Ongoing studies and work include: a) The impact of pediatric HIV disease on non-verbal memory; b) The relationship between results obtained from certain neuropsychological tests, neuroimaging studies, and clinical findings; c) The association between genetic polymorphisms and pediatric HIV CNS disease, d) A new protocol studying the relationship between psychological variables and adherence to an antiretroviral medication regimen; e) A protocol under development that will investigate the correlation between neuropsychological and clinical variables and findings from CNS magnetic resonance spectroscopy. The pediatric HIV research effort has also engaged in a longstanding effort to understand the psychosocial dimensions of pediatric HIV disease. Psychosocial studies recently concluded and in progress include: a) Longitudinal investigation of correlates of psychosocial functioning and coping strategies in long-term survivors who are transitioning from adolescence to young adulthood; b) The prevalence of Post Traumatic Stress Disorder and associated symptoms among HIV-infected children and their families, including an assessment of the levels of psychiatric distress, parenting stress, and a comparison to national norms; c) The prevalence and outcome of pregnancy in perinatally HIV-infected adolescents and risk factors associated with pregnancy (in collaboration with the CDC); d) Studies comparing the psychosocial correl